Modelling of tumor control probability in preclinical targeted radionuclide therapy

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that originate from cells of the neuroendocrine system. Targeted radionuclide therapy (TRT) has become the standard treatment in the management of patients with inoperable or metastasized well-differentiated NETs (up to 90% of symptomatic patients). Peptide receptor radionuclide therapy (PRRT) employs an exclusive feature of well-differentiated NETs that is the overexpression of somatostatin receptors (SST, subtype 2 or 5). This allows for the treatment with somatostatin analogs such as octreotide as well as radiolabeled somatostatin analogs (SSAs) such as 90Y-DOTATOC and 177Lu-DOTATATE. The basic principle of a radiopharmaceutical such as 177-Lu-DOTATATE is to chelate a vector molecule ((Tyr3)octreotate), which specifically targets the cancerous tissue, with a radionuclide (177Lu), which emits ionizing radiation, damaging the DNA of the cancer cells, thereby killing the cancerous cells, but not the surrounding healthy tissue. As an alternative to Lu-177, the recently introduced radiolanthanide Tb-161 has been proposed for NET therapeutic applications. It has a similar half-life (6.89 days) and chemical properties while emitting β- particles (Eβ-av=154 keV) for therapeutic purposes and γ-irradiation (Eγ = 49 keV, I = 17.0%; Eγ = 75 keV, I = 10.2%) suitable for SPECT imaging. Tb-161 also emits a substantial number of low-energy conversion and Auger electrons (≤ 50 keV; about 10x higher emission yield than Lu-177), which makes this radionuclide exceptionally interesting for the treatment of disseminated cancers, such as metastasized NETs, with multiple metastases ranging from a single cell (diameter: ~10 μm) to micro cell clusters (diameter: < 1 mm). Since the very beginning, researchers attempted to understand the radiobiologic effects of external beam radiotherapy (EBRT) and how this could be optimized to maximize therapeutic benefit. To correctly evaluate efficacy and safety of therapy modalities and in the framework of individualized treatment, for which prediction of outcome is important, appropriate biological/biophysical models are needed. The probability that a given therapy may eradicate or control the tumor, is indicated by the formalism ‘tumor control probability’ (TCP). Originally, TCP models have been developed to predict external beam radiotherapy outcomes, both across populations and on a patient-specific level. TRT however is highly different from conventional external beam radiotherapy since it is a form of protracted radiation delivery during which the dose-rate is variable (e.g. due to physical half-life of the radionuclide, its specific activity and vector pharmacokinetics) and the spatial activity distribution is often non-uniform on both cellular and tissue level. Thereby, vectors can be coupled to an abundance of radionuclides that emit beta, alpha or Auger electrons, associated or not with X or gamma rays. Consequently, commonly used assumptions for modeling of EBRT dose response cannot be generalized towards TRT as well. Despite frequent and successful use of Lu-177-DOTATATE in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery, nor is there an abundance of data from preclinical studies. Currently, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry or radiobiological and DNA damage effects in the tumor. Moreover, data on the influence of absorbed doses on the response and toxicity of treatment with radiopharmaceuticals, which are actually a prerequisite for evidence-based individualized therapy, are also still lacking. The aim of this PhD is to develop a framework for improved modeling of the dose-response, i.e. the tumor control probability, for specific TRT scenarios. We will determine the different parameters within the TCP model based on extensive experimental data, gained from well designed experimental studies, representing the specific TRT exposure characteristics. The radiopharmaceuticals of interest consist of the clinically relevant DOTATATE vector, combined with the Lu-177 or Tb-161 radionuclide, tested in well-characterized in vitro and in vivo NET models. Due to the fact that Tb-161 emits a higher percentage of internal conversion and Auger electrons, Tb-161-DOTATATE is expected to deliver a higher absorbed dose to the bound tumor cell and immediate neighboring cells. We aim with our established TCP model to illustrate the expected improved therapeutic efficacy of Tb-161 DOTATATE compared to Lu-177 DOTATATE.